tbuckley/cabot-search huggingface dataset:
Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas
Authors: Andrew L Coveler, David C Smith, Tycel Phillips, Brendan D Curti, Sanjay Goel, Amitkumar N Mehta, Timothy M Kuzel, Svetomir N Markovic, Olivier Rixe, David L Bajor, Thomas F Gajewski, Martin Gutierrez, Hun Ju Lee, Ajay K Gopal, Paolo Caimi, Elisabeth I Heath, John A Thompson, Sahar Ansari, Celine Jacquemont, Ariel Topletz-Erickson, Peigen Zhou, Michael W Schmitt, Juneko E Grilley-Olson
Journal: Journal for ImmunoTherapy of Cancer (2023)

SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. NCT02376699.
Spatial and sector-specific contributions of emissions to ambient air pollution and mortality in European cities: a health impact assessment
Authors: Sasha Khomenko, Enrico Pisoni, Philippe Thunis, Bertrand Bessagnet, Marta Cirach, Tamara Iungman, Evelise Pereira Barboza, Haneen Khreis, Natalie Mueller, Cathryn Tonne, Kees de Hoogh, Gerard Hoek, Sourangsu Chowdhury, Jos Lelieveld, Mark Nieuwenhuijsen
Journal: The Lancet Public Health (2023)

Ambient air pollution is a major risk to health and wellbeing in European cities. We aimed to estimate spatial and sector-specific contributions of emissions to ambient air pollution and evaluate the effects of source-specific reductions in pollutants on mortality in European cities to support targeted source-specific actions to address air pollution and promote population health.We conducted a health impact assessment of data from 2015 for 857 European cities to estimate source contributions to annual PM2·5 and NO2 concentrations using the Screening for High Emission Reduction Potentials for Air quality tool. We evaluated contributions from transport, industry, energy, residential, agriculture, shipping, and aviation, other, natural, and external sources. For each city and sector, three spatial levels were considered: contributions from the same city, the rest of the country, and transboundary. Mortality effects were estimated for adult populations (ie, ≥20 years) following standard comparative risk assessment methods to calculate the annual mortality preventable on spatial and sector-specific reductions in PM2·5 and NO2.We observed strong variability in spatial and sectoral contributions among European cities. For PM2·5, the main contributors to mortality were the residential (mean contribution of 22·7% [SD 10·2]) and agricultural (18·0% [7·7]) sectors, followed by industry (13·8% [6·0]), transport (13·5% [5·8]), energy (10·0% [6·4]), and shipping (5·5% [5·7]). For NO2, the main contributor to mortality was transport (48·5% [SD 15·2]), with additional contributions from industry (15·0% [10·8]), energy (14·7% [12·9]), residential (10·3% [5·0]), and shipping (9·7% [12·7]). The mean city contribution to its own air pollution mortality was 13·5% (SD 9·9) for PM2·5 and 34·4% (19·6) for NO2, and contribution increased among cities of largest area (22·3% [12·2] for PM2·5 and 52·2% [19·4] for NO2) and among European capitals (29·9% [12·5] for PM2·5 and 62·7% [14·7] for NO2).We estimated source-specific air pollution health effects at the city level. Our results show strong variability, emphasising the need for local policies and coordinated actions that consider city-level specificities in source contributions.Spanish Ministry of Science and Innovation, State Research Agency, Generalitat de Catalunya, Centro de Investigación Biomédica en red Epidemiología y Salud Pública, and Urban Burden of Disease Estimation for Policy Making 2023-2026 Horizon Europe project.
Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma
Authors: Jialei Weng, Shaoqing Liu, Qiang Zhou, Wenxin Xu, Minghao Xu, Dongmei Gao, Yinghao Shen, Yong Yi, Yi Shi, Qiongzhu Dong, Chenhao Zhou, Ning Ren
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development. Methods Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1 + macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing. Results Single-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1 + macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1 + macrophage-enriched HCCs were characterized by high infiltration of CD8 + T cells with increased programmed death-1 (PD-1) expression. PPT1 + macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1 − macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model. Conclusions PPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1 + macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.
Association of workplace violence and bullying with later suicide risk: a multicohort study and meta-analysis of published data
Authors: Linda L Magnusson Hanson, Jaana Pentti, Mads Nordentoft, Tianwei Xu, Reiner Rugulies, Ida E H Madsen, Paul Maurice Conway, Hugo Westerlund, Jussi Vahtera, Jenni Ervasti, G David Batty, Mika Kivimäki
Journal: The Lancet Public Health (2023)

BackgroundWorkplace offensive behaviours, such as violence and bullying, have been linked to psychological symptoms, but their potential impact on suicide risk remains unclear. We aimed to assess the association of workplace violence and bullying with the risk of death by suicide and suicide attempt in multiple cohort studies.MethodsIn this multicohort study, we used individual-participant data from three prospective studies: the Finnish Public Sector study, the Swedish Work Environment Survey, and the Work Environment and Health in Denmark study. Workplace violence and bullying were self-reported at baseline. Participants were followed up for suicide attempt and death using linkage to national health records. We additionally searched the literature for published prospective studies and pooled our effect estimates with those from published studies.FindingsDuring 1 803 496 person-years at risk, we recorded 1103 suicide attempts or deaths in participants with data on workplace violence (n=205 048); the corresponding numbers for participants with data on workplace bullying (n=191 783) were 1144 suicide attempts or deaths in 1 960 796 person-years, which included data from one identified published study. Workplace violence was associated with an increased risk of suicide after basic adjustment for age, sex, educational level, and family situation (hazard ratio 1·34 [95% CI 1·15–1·56]) and full adjustment (additional adjustment for job demands, job control, and baseline health problems, 1·25 [1·08–1·47]). Where data on frequency were available, a stronger association was observed among people with frequent exposure to violence (1·75 [1·27–2·42]) than occasional violence (1·27 [1·04–1·56]). Workplace bullying was also associated with an increased suicide risk (1·32 [1·09–1·59]), but the association was attenuated after adjustment for baseline mental health problems (1·16 [0·96–1·41]).InterpretationObservational data from three Nordic countries suggest that workplace violence is associated with an increased suicide risk, highlighting the importance of effective prevention of violent behaviours at workplaces.FundingSwedish Research Council for Health, Working Life and Welfare, Academy of Finland, Finnish Work Environment Fund, and Danish Working Environment Research Fund.
Multifunctional magnesium organic framework-based photothermal and pH dual-responsive mouthguard for caries prevention and tooth self-healing promotion
Authors: Qun Li, Jinbiao Liu, Huijie Liu, Yue Sun, Yingying Xu, Kexin Wang, Wenjing Huang, Lan Liao, Xiaolei Wang
Journal: Bioactive Materials (2023)

Caries is considered to be the most prevalent non-communicable disease in humans, mainly deriving from acidogenic bacterial biofilm and resulting in the demineralization and decomposition of hard dental tissue. Herein, a composite responsive foam brace loaded with magnesium organic framework (MPC) is designed for caries prevention and tooth remineralization. MPC can intelligently release organic antibacterial molecules (gallic acid) and mineralized ions (Mg2+, Ca2+ and PO43-) under acidic conditions (pH < 5.5) of biofilm infection, regulating pH and killing bacteria. Additionally, due to the excellent photothermal conversion efficiency, MPC can further enhance the destruction of bacterial biofilm by inhibiting virulence genes and destroying bacterial adhesion under near-infrared light irradiation (808 nm). More importantly, MPC can not only reverse the cariogenic environment at both pH and microbial levels, but also promote self-healing of demineralized teeth in terms of both the micro-structure and mechanical properties.
Global, regional, and national estimates of tuberculosis incidence and case detection among incarcerated individuals from 2000 to 2019: a systematic analysis
Authors: Leonardo Martinez, Joshua L Warren, Anthony D Harries, Julio Croda, Marcos A Espinal, Rafael A López Olarte, Pedro Avedillo, Christian Lienhardt, Vineet Bhatia, Qiao Liu, Jeremiah Chakaya, Justin T Denholm, Yan Lin, Lisa Kawatsu, Limei Zhu, C Robert Horsburgh, Ted Cohen, Jason R Andrews
Journal: The Lancet Public Health (2023)

People who are incarcerated are at high risk of developing tuberculosis. We aimed to estimate the annual global, regional, and national incidence of tuberculosis among incarcerated populations from 2000 to 2019.
Multimodal recurrence scoring system for prediction of clear cell renal cell carcinoma outcome: a discovery and validation study
Authors: Cheng-Peng Gui, Yu-Hang Chen, Hong-Wei Zhao, Jia-Zheng Cao, Tian-Jie Liu, Sheng-Wei Xiong, Yan-Fei Yu, Bing Liao, Yun Cao, Jia-Ying Li, Kang-Bo Huang, Hui Han, Zhi-Ling Zhang, Wen-Fang Chen, Ze-Ying Jiang, Ye Gao, Guan-Peng Han, Qi Tang, Kui Ouyang, Gui-Mei Qu, Ji-Tao Wu, Jian-Ping Guo, Cai-Xia Li, Pei-Xing Li, Zhi-Ping Liu, Jer-Tsong Hsieh, Mu-Yan Cai, Xue-Song Li, Jin-Huan Wei, Jun-Hang Luo
Journal: The Lancet Digital Health (2023)

BackgroundImproved markers for predicting recurrence are needed to stratify patients with localised (stage I–III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities—clinical, genomic, and histopathological—to improve the predictive accuracy for localised renal cell carcinoma recurrence.MethodsIn this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI).FindingsThe multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825–0·876 vs 0·608–0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49–8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19–6·59; p<0·0001).InterpretationOur multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy.FundingNational Natural Science Foundation of China, and National Key Research and Development Program of China.
Disturbing cytoskeleton by engineered nanomaterials for enhanced cancer therapeutics
Authors: Xueli Xu, Shanbin Xu, Jipeng Wan, Diqing Wang, Xinlong Pang, Yuan Gao, Nengyi Ni, Dawei Chen, Xiao Sun
Journal: Bioactive Materials (2023)

Cytoskeleton plays a significant role in the shape change, migration, movement, adhesion, cytokinesis, and phagocytosis of tumor cells. In clinical practice, some anti-cancer drugs achieve cytoskeletal therapeutic effects by acting on different cytoskeletal protein components. However, in the absence of cell-specific targeting, unnecessary cytoskeletal recombination in organisms would be disastrous, which would also bring about severe side effects during anticancer process. Nanomedicine have been proven to be superior to some small molecule drugs in cancer treatment due to better stability and targeting, and lower side effects. Therefore, this review summarized the recent developments of various nanomaterials disturbing cytoskeleton for enhanced cancer therapeutics, including carbon, noble metals, metal oxides, black phosphorus, calcium, silicon, polymers, peptides, and metal-organic frameworks, etc. A comprehensive analysis of the characteristics of cytoskeleton therapy as well as the future prospects and challenges towards clinical application were also discussed. We aim to drive on this emerging topic through refreshing perspectives based on our own work and what we have also learnt from others. This review will help researchers quickly understand relevant cytoskeletal therapeutic information to further advance the development of cancer nanomedicine.
Health effects of low emission and congestion charging zones: a systematic review
Authors: Rosemary C Chamberlain, Daniela Fecht, Bethan Davies, Anthony A Laverty
Journal: The Lancet Public Health (2023)

Low emission zones (LEZs) and congestion charging zones (CCZs) have been implemented in several cities globally. We systematically reviewed the evidence on the effects of these air pollution and congestion reduction schemes on a range of physical health outcomes. We searched MEDLINE, Embase, Web of Science, IDEAS, Greenfile, and Transport Research International Documentation databases from database inception to Jan 4, 2023. We included studies that evaluated the effect of implementation of a LEZ or CCZ on air pollution-related health outcomes (cardiovascular and respiratory diseases, birth outcomes, dementia, lung cancer, diabetes, and all-cause) or road traffic injuries (RTIs) using longitudinal study designs and empirical health data. Two authors independently assessed papers for inclusion. Results were narratively synthesised and visualised using harvest plots. Risk of bias was assessed using the Graphic Appraisal Tool for Epidemiological studies. The protocol was registered with PROSPERO (CRD42022311453). Of 2279 studies screened, 16 were included, of which eight assessed LEZs and eight assessed CCZs. Several LEZ studies identified positive effects on air pollution-related outcomes, with reductions in some cardiovascular disease subcategories found in five of six studies investigating this outcome, although results for other health outcomes were less consistent. Six of seven studies on the London CCZ reported reductions in total or car RTIs, although one study reported an increase in cyclist and motorcyclist injuries and one reported an increase in serious or fatal injuries. Current evidence suggests LEZs can reduce air pollution-related health outcomes, with the most consistent effect on cardiovascular disease. Evidence on CCZs is mainly limited to London but suggests that they reduce overall RTIs. Ongoing evaluation of these interventions is necessary to understand longer term health effects.
Neutrophil diversity and plasticity: Implications for organ transplantation
Authors: Junwen Qu, Jingsi Jin, Ming Zhang, Lai Guan Ng
Journal: Cellular and Molecular Immunology (2023)

Abstract Neutrophils, as the first defenders against external microbes and stimuli, are highly active and finely regulated innate immune cells. Emerging evidence has challenged the conventional dogma that neutrophils are a homogeneous population with a short lifespan that promotes tissue damage. Recent findings on neutrophil diversity and plasticity in homeostatic and disease states have centered on neutrophils in the circulation. In contrast, a comprehensive understanding of tissue-specialized neutrophils in health and disease is still lacking. This article will first discuss how multiomics advances have contributed to our understanding of neutrophil heterogeneity and diversification in resting and pathological settings. This discussion will be followed by a focus on the heterogeneity and role of neutrophils in solid organ transplantation and how neutrophils may contribute to transplant-related complications. The goal of this article is to provide an overview of the research on the involvement of neutrophils in transplantation, with the aim that this may draw attention to an underappreciated area of neutrophil research.
Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF-β-induced epithelial–mesenchymal transition via directly targeting TGFβR1
Authors: Jingnan Zhang, Ze Zhang, Zhenlin Huang, Manlin Li, Fan Yang, Zeqi Wu, Qian Guo, Xiyu Mei, Bin Lu, Changhong Wang, Zhengtao Wang, Lili Ji
Journal: Acta Pharmaceutica Sinica B (2023)

As the most aggressive breast cancer, triple-negative breast cancer (TNBC) is still incurable and very prone to metastasis. The transform growth factor β (TGF-β)-induced epithelial–mesenchymal transition (EMT) is crucially involved in the growth and metastasis of TNBC. This study reported that a natural compound isotoosendanin (ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia. ITSN can directly interact with TGF-β receptor type-1 (TGFβR1) and abrogated the kinase activity of TGFβR1, thereby blocking the TGF-β-initiated downstream signaling pathway. Moreover, the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1. Furthermore, Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1. Additionally, ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1 (PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment. Our findings not only highlight the key role of TGFβR1 in TNBC metastasis, but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis. Moreover, this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.
Machine learning for ECG diagnosis and risk stratification of occlusion myocardial infarction
Authors: Salah S. Al-Zaiti, Christian Martin-Gill, Jessica K. Zègre-Hemsey, Zeineb Bouzid, Ziad Faramand, Mohammad O. Alrawashdeh, Richard E. Gregg, Stephanie Helman, Nathan T. Riek, Karina Kraevsky-Phillips, Gilles Clermont, Murat Akcakaya, Susan M. Sereika, Peter Van Dam, Stephen W. Smith, Yochai Birnbaum, Samir Saba, Ervin Sejdic, Clifton W. Callaway
Journal: Nature Medicine (2023)

Patients with occlusion myocardial infarction (OMI) and no ST-elevation on presenting electrocardiogram (ECG) are increasing in numbers. These patients have a poor prognosis and would benefit from immediate reperfusion therapy, but, currently, there are no accurate tools to identify them during initial triage. Here we report, to our knowledge, the first observational cohort study to develop machine learning models for the ECG diagnosis of OMI. Using 7,313 consecutive patients from multiple clinical sites, we derived and externally validated an intelligent model that outperformed practicing clinicians and other widely used commercial interpretation systems, substantially boosting both precision and sensitivity. Our derived OMI risk score provided enhanced rule-in and rule-out accuracy relevant to routine care, and, when combined with the clinical judgment of trained emergency personnel, it helped correctly reclassify one in three patients with chest pain. ECG features driving our models were validated by clinical experts, providing plausible mechanistic links to myocardial injury.